To clarify the joint effects of environmental and genetic factors in the etiology of breast cancer, the NIEHS Sister Study is prospectively studying sisters of women who have had breast cancer. Such sisters have about twice the risk of developing breast cancer as other women. The frequency of any relevant genes and shared risk factors will also be higher, enhancing the statistical power of the study to detect risks. Sisters are highly motivated and response rates and compliance over time are expected to be high. Thus, studying sisters will enhance our ability to understand the interplay of genes and environment in breast cancer risk and to identify potentially preventable risk factors. The prospective design will allow us assess exposures before the onset of disease thus avoiding biases common to retrospective studies and aiding in causal interpretation. The study will create a framework from which to test new breast cancer hypotheses as they emerge and to also study other health endpoints. A diverse cohort of volunteer women from throughout the US and Puerto Rico between the ages of 35 and 74 who have a sister with breast cancer but do not have breast cancer them selves have been recruited. Recruitment strategies were designed to maximize inclusion of minorities and high-risk women. Data on potential risk factors and current health status were collected using computer assisted telephone interviews and mail questionnaires. Blood, urine, and environmental samples were collected in a home visit and banked for future use in nested studies of women who develop breast cancer (or other diseases) and a sample of those who don't. The cohort will be followed prospectively for 10 or more years. Address changes, vital status, and major health changes are updated annually. More detailed health and exposure updates will be collected at 2-year intervals. Medical records and tumor tissue (for breast cancer cases) are retrieved for those who develop cancer or other conditions of interest. At least 1500 new cases of breast cancer are expected to occur in the cohort after five years. Analyses will assess the independent and combined effects of environmental exposures and genetic polymorphisms that affect estrogen metabolism, DNA repair, and response to specific environmental exposures. Future analyses will focus on known and potential risk factors (e.g. smoking, occupational exposures, alcohol, diet, obesity) and include measurement of phthalates, phytoestrogens, and metals in blood and urine, insulin, growth factors, vitamins and nutrients, and genes. The cohort will be used to also study risk for other diseases (e.g. heart disease, osteoporosis, other hormonal cancers, and autoimmune diseases) as well as explore genetic and environmental effects on prognosis. A pilot phase began August 2003 involving women from 4 metropolitan areas of the US selected for their geographic and ethnic diversity in order to assess a range of recruitment strategies and plan for a larger scale national effort. The study began recruiting nationally in October 2004. All study materials were made available in Spanish in mid-September, 2005. Recruitment was closed in March 2009 and the cohort fully enrolled by July 21,2009. Nearly 51,000 women completed all baseline study activities. The response rates for annual updates range from 90-98%. Biennial follow-up questionnaires have been collected from approximately 9,065 qualifying women this year for a total of 38,368 completed to date. Using analytic data collected at baseline, we have been exploring relationships among breast cancer risk factors and carrying out descriptive analyses. One area of interest this year has been early life factors that may affect timing of puberty or alter breast development, which in turn could affect the risk of breast cancer or other outcomes in life. Papers have been published on early life factors and age at menopause and the influence of childdhood factors on age at menarche. A case-cohort study involving the first 350 breast cancer cases and a sample of 700 women selected from the cohort is exploring breast cancer risk in relation to gene polymorphisms linked to breast cancer in previous genome wide association stidues, methylation, and telomere length. Data analysis for these studies is on-going. Results of several of analyses have been presented at national scientific meetings and manuscripts are in preparation for publication. To date, more than 1,200 women have reported a diagnosis of breast cancer or DCIS and medical records and tumor tissue are being sought for those 6 months post diagnosis. A related study known as the Two Sister Study builds on the Sister Study to recruit the affected sister of participants in the Sister Study as well as parents who are asked to provide a saliva sample to be used as a source of DNA for family-based analysis of genetic factors associated with risk. To date, over 1,500 affected sisters and 1,300 parents have enrolled and data collection is on-going. A small study was initiated this year to validate self-reported maternal and early childhood exposures by collecting information from mothers on their pregnancy with study participants and the participants childhood. To date, over 1,600 completed questionnaires from mothers have been received. Finally, another small study began this year on factors that influence estrogen levels in 600 post-menopausal women and their association with breast cancer. The study will address Prostoglandin E2 and active estrogen in postmenopausal women and the risk of breast cancer risk, and also examine the possible influence of certain nonsteroidal anti-inflammatory drugs on levels of estrogens.